Method for treating endometriosis

ABSTRACT

A drug effective for prevention and therapy of endometriosis is disclosed. The drug for prevention and/or therapy of endometriosis according to the present invention comprises an antiallergic agent as an effective ingredient.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/JP01/11069 which has an Internationalfiling date of Dec. 18, 2001, which designated the United States ofAmerica.

TECHNICAL FIELD

The present invention relates to a drug for prevention and/or therapy ofedometriosis

BACKGROUND ART

Endometriosis is a disease wherein endometrium or endometrium-liketissue ectopically proliferates at a site other than the inner surfaceof the cavity of uterus which is the natural site thereof. The cause ofendometriosis is unknown, and therapies such as separation of theadhered tissues by surgery, administration of hormones andadministration of analgesics are performed. However, these therapies aresymptomatic treatments, and no complete therapy exists.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a drug effective forprevention and therapy of endometriosis.

The present inventor studied by staining ectopical endometrium-liketissue (endometriosis sample) and the tissue sampled from the same siteof the healthy individuals by various staining methods, and observingthem with an light microscope and an electron microscope. As a result,in the endometriosis samples from patients suffering from endometriosis,invasion of mast cells and degranulation thereof, as well asproliferation of interstitial component were observed. These are thetypical symptoms of type I allergy, so that it was found that theessence of endometriosis is an allergic inflammation. The presentinventor thought that it might be possible to cure endometriosis by anantiallergic agent, and administered a plurality of commerciallyavailable antiallergic agents to endometriosis animal model to examinetheir therapeutic effects. As a result, as expected, it wasexperimentally confirmed that the symptoms of endometriosis are clearlyinhibited by the antiallergic agents, thereby completing the presentinvention.

That is, the present invention provides a drug for prevention and/ortherapy of endometriosis comprising an antiallergic agent as aneffective ingredient. The present invention also provides a use of anantiallergic agent for the production of a drug for prevention and/ortherapy of endometriosis. The present invention further provides amethod for prevention and/or therapy of endometriosis comprisingadministering an antiallergic agent to a patient suffering fromendometriosis, in an amount effective for the prevention or therapy ofendometriosis.

By the present invention, a drug effective for prevention and therapy ofendometriosis, which can cure endometriosis was first provided. Thenumber of patients suffering from endometriosis is now rapidlyincreasing, and endometriosis is now one of the main causes ofmenorrhalgia and infertility. Thus, the present invention is thought togreatly contribute in the field of therapy of infertility, and therapyand prevention of menorrhalgia.

BEST MODE FOR CARRYING OUT THE INVENTION

As mentioned above, the drug for prevention or therapy of endometriosisaccording to the present invention is effective for both prevention andtherapy of endometriosis (that is, the drug may be used as a drug fortherapy, as a drug for prevention, and as a drug simultaneously aimingat therapy and prevention), and comprises an antiallergic agent as aneffective ingredient.

The present inventor first discovered in the world that the essence ofendometriosis is an allergic inflammation. The present invention wasmade based on this discovery. Since the symptoms of the endometriosiscan be lightened by lightening the symptoms of the allergy, anyantiallergic agents effective for therapy and/or prevention of allergiesmay be employed as the antiallergic agent contained as the effectiveingredient in the drug for prevention and/or therapy of endometriosisaccording to the present invention.

The antiallergic agent used in the present invention is an inhibitor oran antagonist against the type I allergy reaction, and includesinhibitors for release of chemical mediators from mast cells, synthetaseinhibitors and chemical mediator antagonists (such as antihistamicagents). Various such antiallergic agents are known and used for thetherapies of bronchial asthma, allergic rhinitis and allergic dermatitiswhich are representative diseases of type I allergy, and both thosehaving antihistaminic action and not having antihistaminic action areincluded. Examples of the antiallergic agent which may be used in thepresent invention include cromoglycic acid, tranilast, amlexanox,repirinast, tazanolast, pemirolast K, suplatast, ketotifen, azelastine,oxatomide, terfenadine, mequitazine, emedastine, epinastine, astemizole,ibudilast, ozagrel, seratrodast, pranlukast, ebastine, cetirizine,cyproheptadine, chlorophenylamine, homochiorcyclizine, hydroxyzine andclemastine, as well as pharmaceutically acceptable salts and hydratesthereof. Among these, epinastine, ketotifen and pranlukast, as well aspharmaceutically acceptable salts and hydrates thereof are especiallypreferred.

Examples of the pharmaceutically acceptable salts include acid additionsalts such as hydrochloric acid salt, sulfuric acid salt, fumaric acidsalt, maleic acid salt, tartaric acid salt, citric acid salt and tosylicacid salt, as well as metal salts such as sodium salt, potassium saltand calcium salts when the active compound is an acid, although thepharmaceutically acceptable salts are not restricted thereto.

The drug for prevention and/or therapy of endometriosis according to thepresent invention may be administered through the route permitted to theantiallergic agent contained as the effective ingredient. Administrationroutes include oral administration, and parenteral administration routessuch as intravenous, subcutaneous, intramuscular and rectaladministration. Usually, oral administration is preferred because it issimple. Although the administration dose is appropriately selecteddepending on the degree of the symptom of the patient, type of theantiallergic agent and the like, the dose is, for example, about 10 to20 mg in the case of epinastine hydrochloride per day per adult. Theantiallergic agents are effective at the administration doses employedfor the therapy of allergies by the respective antiallergic agent.

Adenomyosis of uterus is the state that the endometrium orendometrium-like tissue ectopically proliferates in myometrium, so thatit is a form of endometriosis and is included in endometriosis(“Surgical Pathology”, p.713-715, published by Bunkodo; “ClinicalHistopathology”, p.661, published by Kyorin Shoin).

As for the formulation of the drug, any formulation methods ordinarilyemployed in the field of pharmaceuticals may be employed. For example,the antiallergic agent may be granulated together with an additive suchas lactose, a polyoxyethylenesorbitan fatty acid ester, propylene glycolor sodium laurate, and the resultant may be made into tablets, but theformulation method is not restricted thereto. The above-mentionedvarious antiallergic agents are commercially available in formulatedforms, these formulated antiallergic agents may be employed in thepresent invention.

Since antiallergic agents have already been used as therapeutic agentsfor various allergies such as bronchial asthma, allergic rhinitis andallergic dermatitis, safeties thereof to the extent demanded forpharmaceuticals have been confirmed.

The present invention will now be described more concretely by way ofexamples. However, the present invention is not limited to the followingexamples.

REFERENCE EXAMPLE 1 Observation of Human Endometriosis Specimens

Adhered lesions in pelvic cavity were sampled from patients sufferingfrom endometriosis (external endometriosis), and stained byhematoxylin-eosin staining or toluidine blue staining according to theconventional methods, followed by observation of the stained sampleswith an light microscope. The magnification was 10× when observing thehematoxylin-eosin-stained specimens, and 20× or 100× when observing thetoluidine blue-stained specimens. The tissue was also subjected touranium-lead double staining according to the conventional method, andthe obtained specimens were observed with an electron microscope at amagnification of 3000× to 5000×.

As a result, in the toluidine blue-stained specimens of the tissues frompatients suffering from endometriosis, invasion of mast cells wasobserved. Further, by the observation with the electron microscope,degranulation of mast cells was observed in addition to the invasion ofthe mast cells. Still further, collagen fibers which are the main resultof the growth of the interstitial component. On the other hand, in thespecimens from healthy individuals, invasion and degranulation of mastcells, and collagen fibers were not observed. Invasion of mast cells andtheir degranulation are the symptoms of type I allergy. From theabove-described observations with microscopes, it was discovered thatthe essence of endometriosis is an allergic inflammation.

COMPARATIVE EXAMPLE 1 Observation of Non-Treated Endometriosis ModelRats

Endometriosis model rats were prepared by the method described inMichael W. Vernon et al., FERTILITY AND STERILITY, Vol. 44, No. 5,November 1985. That is, endometriosis model rats were prepared asfollows: Sprague-Dawley rats (female) of 8 weeks old were acclimatizedfor 2 weeks under 12 hours light-dark condition. From each rat, rightuterine horn was excised under general anesthesia with sevoflurane andketamine hydrochloride, and a tissue piece sizing 5 mm×5 mm was preparedtherefrom. The tissue piece was subjected to autotransplantation suchthat the endometrium surface is attached to peritoneum.

Seven days after the preparation of the model rats, at which the modellesion reached its peak, the peritoneum tissue including the graft up tothe abdominal muscle was excised to obtain a lesion sample. From thethus obtained samples, light microscope specimens (hematoxylin-eosinstaining, toluidine blue staining) and electron microscope specimens(uranium-lead double staining) were prepared, and observations with anlight microscope (the magnifications were 4× forhematoxylineosin-stained specimens, and 20× for toluidine blue-stainedspecimens, respectively), and with an electron microscope were carriedout as in Reference Example 1.

As a result, invasion of mast cells and proliferation of interstitialcells were observed by the toluidine blue staining, and invasion ofeosinophils and lymphocytes was observed by the observation with theelectron microscope.

EXAMPLE 1 Therapeutic Effect by Administration of EpinastineHydrochloride

Endometriosis model rats were prepared by the same method as inComparative Example 1. From 24 hours after the preparation of theendometriosis model rats, an antiallergic agent (trademark “AlesionTablet” produced by Boehringer Ingelheim) containing epinastinehydrochloride as the active component was orally administered to therats for 6 days at a dose of 0.04 mg/kg bodyweight per day in terms ofepinastine hydrochloride. Seven days after the preparation of the modelrats, at which the model lesion reached its peak, the peritoneum tissuesincluding the graft up to the abdominal muscle were excised to obtainlesion samples. The obtained pathological samples were stained as inReference Example 1, and the resultants were observed with an lightmicroscope and with an electron microscope.

As a result, the invasion of mast cells was apparently reduced whencompared with the case of Comparative Example 1. By the observationswith the light microscope and with the electron microscope, apoptosis offibroblast cells was observed, and prominent inhibition of proliferationof the interstitial cells by the induction of apoptosis of interstitialcells, especially fibroblast cells was observed. From these, it wasproved that epinastine is effective for the therapy of endometriosis.

EXAMPLE 2 Therapeutic Effect by Administration of Ketotifen Fumarate

The same procedures as in Example 1 were repeated except that anantiallergic agent containing ketotifen fumarate as the active component(trademark “Zaditen” produced by Ciba-Geigy Japan Limited) wasadministered in place of the antiallergic agent containing epinastinehydrochloride as an active component.

As a result, the invasion of mast cells was apparently reduced whencompared with the case of Comparative Example 1. By the observationswith the light microscope and with the electron microscope, apoptosis offibroblast cells was observed, and prominent inhibition of proliferationof the interstitial cells by the induction of apoptosis of interstitialcells, especially fibroblast cells was observed. From these, it wasproved that ketofetin is effective for the therapy of endometriosis.

EXAMPLE 3 Therapeutic Effect by Administration of Pranlukast Hydrate

The same procedures as in Example 1 were repeated except that anantiallergic agent containing pranlukast hydrate as the active component(trademark “ONON CAPSULE” produced by ONO PHARMACEUTICAL CO.,LTD.) wasadministered in place of the antiallergic agent containing epinastinehydrochloride as an active component, and that the administration doseper day was 9 mg/kg in terms of pranlukast hydrate.

As a result, the invasion of mast cells was prominently reduced whencompared with the case of Comparative Example 1. The effect forinhibiting invasion of mast cells was more prominent than in Examples 1and 2. By the observations with the light microscope and with theelectron microscope, apoptosis of fibroblast cells was observed, andprominent inhibition of proliferation of the interstitial cells by theinduction of apoptosis of interstitial cells, especially fibroblastcells was observed. From these, it was proved that pranlukast iseffective for the therapy of endometriosis.

1. A method for therapy of endometriosis comprising administering anantiallergic agent to a patient suffering from endometriosis, in anamount effective for the therapy of endometriosis wherein saidantiallergic agent is epinastine or pharmaceutically acceptable saltsthereof, ketotifen or pharmaceutically acceptable salts thereof orpranlukast or pharmaceutically acceptable salts or hydrates thereof. 2.The method according to claim 1, wherein said antiallergic agent isadministered orally or parenterally.
 3. The method according to claim 1,wherein said pharmaceutically acceptable salts are acid addition saltsor metal salts.
 4. The method according to claim 1, wherein saidantiallergic agent is administered orally.
 5. The method according toclaim 1, wherein said antiallergic agent is epinastine or ketotifen, orpharmaceutically acceptable salts thereof.
 6. A method for therapy ofendometriosis, comprising: administering an antiallergic agent to apatient suffering from endometriosis, in an amount effective for thetherapy of endometriosis, wherein endometriosis is defined as anallergic inflammation and is a type I allergy wherein said antiallergicagent is epinastine or pharmaceutically acceptable salts thereof,ketotifen or pharmaceutically acceptable salts thereof or pranlukast orpharmaceutically acceptable salts or hydrates thereof.
 7. The methodaccording to claim 6, wherein said pharmaceutically acceptable salts areacid addition salts or metal salts.
 8. The method according to claim 6,wherein said antiallergic agent is administered orally.
 9. The methodaccording to claim 6, wherein said antiallergic agent is pranlukast, orpharmaceutically acceptable salts or hydrates thereof.
 10. A method fortherapy of endometriosis, comprising: administering an antiallergicagent to a patient suffering from endometriosis in an amount effectivefor the therapy of endometriosis, wherein endometriosis is defined as anallergic inflammation and is a type I allergy or adenomyosis whereinsaid antiallergic agent is epinastine or pharmaceutically acceptablesalts thereof, ketotifen or pharmaceutically acceptable salts thereof orpranlukast or pharmaceutically acceptable salts or hydrates thereof.